I originally posted this in 2024 and there have been major, relevant study publications since then. I hate seeing my material out of date, so I’ve added the findings into this new updated version, and tried to polish things.
It’s a big piece to take in, more like a chapter than my bite-size weekly, so be prepared. Also, apologies if it’s a repeat for you, I’ll be back with new material next week. Enjoy!
At his 1933 presidential inauguration Franklin Delano Roosevelt was a picture of fortitude. Americans, he thundered, had nothing to fear but fear itself. And he proved it, leading a crippled and wary nation to victory in history’s deadliest war. But during a 12-year presidency, increasingly flea-bitten by a failing heart, FDR and his doctors should have been afraid.
In the early twentieth century high blood pressure, or hypertension, was seen as a clever trick of nature. Increasing the heart’s force and tightening blood vessels, the theory went, were evolutionary workarounds to push blood through stiff, aging arteries. Lowering a person’s blood pressure, it was thought, could leave blood trickling like water in an outsized drainpipe. Vessels needed high pressure to force oxygen and nutrients through capillary walls into hungry tissues. Today’s term for most high blood pressure, ‘essential’ hypertension is a vestige of this flawed thinking.
High BP, we now know, is not essential. It’s bad. In 1932, during Roosevelt’s first presidential campaign, his blood pressure was 140/100. The 50-year old statesman was in excellent health and his physicians were delighted. But five years later in 1937, Roosevelt’s health had begun to fail and Surgeon General Ross T. McIntire recorded FDR’s pressure at 162/98. Then, in 1940 it was 178/88, and a year later 188/105. Dr. McIntire, a believer in essential hypertension, called this “normal for a man of his age.”
In March 1944 after years of conspicuously declining vigor and a blood pressure at 200/108, Roosevelt saw one of America’s first heart specialists, Howard Bruenn. From Bruenn’s notes: “He appeared to be very tired and his face was very gray. Moving caused considerable breathlessness.” Bruenn also described FDR as “in good humor, a testament to the president’s disposition and stoicism.”
The cardiologist correctly surmised high blood pressure was the problem, and diagnosed FDR with hypertensive cardiac failure. But he prescribed reduced salt and digitalis, a drug that increases cardiac force. While the president’s lungs cleared slightly, improving his fatigue and shortness of breath, his blood pressure rose to 226/118.
Bruenn then began FDR on a trial of phenobarbital, a powerful soporific used today only as a last resort for uncontrollable seizures and general anesthesia. This did little for his blood pressure, but he was certainly sleeping well. Through the fall of 1944 despite increasing his medicines, Bruenn routinely noted pressures up to 240/130. Then, in late November, 260/150.
By January 1945 at his fourth, much quieter inauguration FDR was a feeble man. Drawn and short of breath with a bluish hue, his blood pressure was 280/130. His heart was enlarged and inefficient, his lungs full of the backwash from a failing pump. At the Yalta Conference in February Winston Churchill’s physician, Lord Charles Moran, was aghast. “The Americans here cannot bring themselves to believe that he is finished” Moran said, then predicted FDR had two months to live.
Two months later, on April 12th at his Little White House in Warm Springs, Georgia, the 64-year old president clutched his head, lost consciousness, and died from a massive cerebral hemorrhage. The stroke was caused by a decade of runaway hypertension. Bruenn, a dedicated and respected clinician, was at the president’s side throughout. He recorded blood pressures “well over 300.”
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Framingham
FDR’s death sent shivers down the spine of American medicine and spawned a movement. In 1948 President Harry S. Truman signed into law the National Heart Act, which did not equivocate: “The Nation’s health is seriously threatened by diseases of the heart and circulation, including high blood pressure.”
The law created the National Heart Institute, soon to be the most funded National Institute of Health. Recognizing the chicken-egg questions that plague heart disease, the Institute generated an ambitious project aiming to enroll and follow more than five thousand healthy American men and women. The Framingham Heart Study, unprecedented in scope, would become the most important research of the 20th century—for better and for worse.
Originally conceived as a trial comparing treatments, experts realized there were none to compare. With not one pill, tincture, or procedure ever proven to cure or even improve heart disease, they had no control group. There were abundant theories (like essential hypertension) but no data. The plan therefore shifted from treatment to observation. The ‘trial’ became a cohort study observing a group for decades, while patiently recording blood pressure, lifestyle, cholesterol, and other characteristics. The goal was to find the predictors and seeds of heart disease. For participants, the researchers chose Framingham, Massachusetts, a blue-collar community a short drive from Harvard, the project’s nerve center.
Despite how mundane the research sounds compared to today’s high speed, high tech, profit-driven palette, the Framingham Study was revolutionary. Before it, research was focused almost exclusively on illness. New antibiotics fought infection, insulin treated diabetes, and surgery could cure or mitigate common emergencies. The Framingham Heart Study was different, moving upriver to prevent disease—pulling people out before the rapids. It was risky, expensive, and long-term, bucking norms. In a culture of staunch traditionalism the Framingham researchers were epidemiological activists, charting a new path for public health. And it worked.
The researchers soon identified characteristics that emerged, intuitively and statistically, as powerful harbingers. In a famous 1961 paper the investigators dubbed these ‘factors of risk’, coining a term for the ages.
Some of the most powerful risk factors were immutable: age, sex, and family history. ‘Heart disease’ is a misnomer since the condition is foremost an affliction of blood vessels. Just as skin wrinkles, vessels age. The loss of elasticity in artery walls makes them vulnerable to nicks and tears. These blemishes become the building blocks of arterial plaque and fibrosis, the sine qua non of heart disease. Thus the chance of heart problems increases with age and often hews closely to family history. And for reasons that are foggy even today, men have twice the risk as women.
But some risk factors held promise as targets. The most powerful was a habit. Regardless of age or sex, smoking cigarettes was associated with two to eight times the risk of heart attacks, strokes, and death. There was also a strong dose-response relationship: the more cigarettes, the more heart problems.
Diabetes, a condition with its own path to blood vessel damage, also doubled the chance of heart attack or stroke. The condition was less common in the 1950s but when present it was no less ominous.
Next up was FDR’s demon, hypertension. At almost the same levels as smoking and diabetes, high blood pressure was a strong predictor of disease and death. And like smoking, higher pressure meant greater risk. FDR’s blood pressure, the research showed, was a time bomb. Randomized trials soon followed, showing blood pressure control prevented heart attacks, strokes, and deaths. Antihypertensive treatment, which continues to extend and improve the lives of hundreds of millions, is a direct outgrowth of the Framingham project.
But to the surprise of many, at the lowest rung on the ladder was cholesterol. In the early publications cholesterol was mathematically linkable to heart attacks and deaths, but compared to sex, age, smoking, diabetes, and blood pressure, the association was tenuous at best. And it waned with time. As the study wore on, a clear picture took shape for smoking, diabetes, and hypertension. But not for cholesterol.
In the study’s 1993 final report on cholesterol, a paper with more than three decades of data, the investigators were forced to concede cholesterol had no association with mortality. After early reports in which cholesterol seemed to be a risk factor (albeit the weakest) this conclusion was a stunning reversal. There simply was no statistical relationship between early death and elevated cholesterol. When broken down into narrow age ranges, the youngest men in the study, particularly those in their thirties and forties, saw a weakly elevated risk for mortality with very high cholesterol (>300 total). But between ages 50 and 70, when most major heart problems occur, the two were unrelated. Then, beyond age 70 low cholesterol became a risk factor for death. The researchers strongly cautioned against lowering cholesterol in people over 65.
Of the four big, modifiable risk factors touted in the early stages of the data—smoking, hypertension, diabetes, and cholesterol—three had stood the test of time, but one did not.
Incredibly, however, in a presumptuous and ill-fated leap, ten years before the final Framingham report the American Heart Association and the NIH began collaborating to develop a consensus on cholesterol. Conferences were held and papers published extolling the Lipid Hypothesis, a theory asserting cholesterol is the primary cause of heart disease, and lowering cholesterol prevents it. This, the experts declared—before the data were in—was proven “beyond a reasonable doubt.”
The Cholesterol Zeitgeist
It is ironic that cholesterol, always the weakest factor and the one debunked in the final paper, became the best known. But by 1993, when the researchers published their conclusions, cholesterol was cardiology’s whipping boy. The lesions that define coronary artery disease, after all, have cholesterol in them. In 1856, Rudolf Virchow first described atheromatous plaques pockmarking the vessels of people who died from heart disease. Like infesting lumps under the paint of a tunnel’s inner wall, some were large enough to block passages altogether. Cutting them open and placing his dissections under a microscope Virchow found collagen, overgrown smooth muscle cells, cell debris, fibrin, other proteins—and cholesterol.
First described as a component of gallstones in 1769, cholesterol was later found in the bloodstream, then identified as a key component of eggs and red meats. This led Alexander Ignatowski, a researcher working with Ivan Pavlov, to overfeed rabbits with meats, eggs, and dairy products. Ignatowski hoped to accelerate the ageing process, and indeed he found atherosclerosis, a known hallmark of ageing, in his gluttonous rabbits.
Later, in 1970 Ancel Keys, history’s most famous diet researcher, published the Seven Countries study. It seemed to confirm Ignatowski’s findings, suggesting an association between high dietary cholesterol and heart disease. Debate rages even today, however, about the study. It turns out Keys’ team examined 22 countries but only reported the results from seven. Missing were countries like France where heart disease was uncommon but foods high in cholesterol (think cheese) were dietary staples. Ancel Keys rose to prominence railing against cholesterol, before he had data. Critics say his reports and results were manipulated to confirm his theory.
But the American Heart Association gladly accepted Keys’ conclusions, and the zeitgeist followed. When, in 1991, George Wendt as a Bears fan on Saturday Night Live blamed his heart attack on a piece of “sassage” in his heart, the transition was complete. Foods high in cholesterol like eggs, cheese, red meat, and butter were slammed in campaigns while foods packed with sugar and carbohydrates were lauded as ‘heart healthy’. (After surgery in 2012 Wendt still joked about his “coronary kielbosis”).
Best of all, deaths from heart disease were declining, and had been since the 1960s. Though the trend began before cholesterol pills or angioplasty even existed, experts everywhere patted themselves on the back. The cause of heart disease, and the path to reversing it, had seemingly been solved.
Reality
Correlation does not equal causation. Reading comprehension, for instance, is strongly associated with shoe size. That’s because five-year-olds and twenty-five-year-olds often have different reading comprehension—but not because of their feet.
Declining heart disease and the cholesterol zeitgeist was another confounded association. While a drop in heart deaths may have occurred as cholesterol angst was rising, the two are unrelated, a fact that became clearest in the late 1980s when some of the most anticipated drugs in history failed, in spectacular fashion.
To understand just how seriously things backfired when the first major cholesterol-lowering pills were studied, consider an editorial from February, 1992 in the BMJ, one of the world’s top medical journals. Titled “Should There Be a Moratorium on the Use of Cholesterol Lowering Drugs?” the paper was written by two prominent experts and epitomized the soul-searching tone that surrounded the infamous fibrate debacle. Fibrate drugs like gemfibrozil rev up enzymes to remove cholesterol from the blood, and in one sense the drugs worked exactly as intended. In another, far more accurate sense, they were a catastrophe.
Compared to a placebo the fibrate drugs reduced cholesterol and triglyceride levels, which led to precisely the intended effect, fewer heart attacks. But there was a rub: More people were dying.
Despite fewer heart attacks people who took fibrate drugs were dying so frequently that any potential advantage from heart attacks was eclipsed. And no one could figure out why. Some participants died from seemingly random causes like car accidents while others taking fibrates contracted more fatal cancers. Either way, there was a clear and consistent trend: more people died while on fibrates.
This essentially ended mass prescribing of fibrates and plunged the AHA and cardiology community into crisis. They had been pushing the Lipid Hypothesis for years, while quietly hoping trials would prove them right. And things were even bleaker for pharmaceutical companies. For them the crisis was not theoretical, it was existential. By 1992 the industry had bet the farm on an exciting new class of cholesterol-lowering drugs: The statins.
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Statins
With instant amnesia the cardiology community abandoned fibrates and began prescribing statins. Atorvastatin (Lipitor) alone generated more than $150 billion in sales, the most ever for a single drug, and statins became the most successful drug class in history. But the debate over whether they work was burning hot. Which is odd, since there are dozens of publicly available trial reports, with data from more than a quarter million study participants. With this plethora of data the answer should be simple math.
But it’s not. Because the data are hidden.
Lovastatin was released in 1987. Next came simvastatin, pravastatin, and fluvastatin. All were approved or in development during the fibrate crisis, and each company reacted decisively, with journal articles hyping their new drugs, glowing assessments by paid experts, and sometimes far-fetched theories to explain away the fibrate deaths. Their most chilling and novel tactic, however, was to keep an iron grip on the data. Transparency would not burn them again.
In a clear reversal of accepted practice in the sciences, drug manufacturers refused to allow independent groups to even see, much less analyze, the data from their trials. The scientific community has therefore only seen the slices of data presented by company authors. These reports, published in prestigious journals, are typically 5-10 page papers distilled from tens of thousands of pages of trial data. Outside of a small group of researchers who signed nondisclosure agreements (and in most cases have financial ties to the makers) no one has ever been allowed to see the original data.
Obviously, this is a problem. Pharmaceutical companies have not exactly earned the public trust. Recent history is littered with examples of fraudulent and misrepresentative drug company reports. In the Vioxx (Merck), Neurontin (Pfizer), and Oxycontin (Purdue) scandals, companies were caught red-handed doctoring or manipulating results, or making claims they knew to be untrue. With a few keystrokes or a clever analysis, a drug’s failure or even its fatal danger magically becomes a triumphant study and a fawning headline. It is estimated that 50,000 Americans died from an effect plainly visible in Merck’s data on Vioxx, but omitted from journal reports.[1]
This history of misrepresentation through puffed-up papers is why a careful reading of the statin studies leads to a conclusion that is, frankly, hard to fathom: Even in the companies’ curated, hand-written study reports, the drugs were no better than a placebo.
Understanding Statin Data
Before diving into the data some prep is necessary. Think back to the self-doubting 1990s editorials. Recall cholesterol-lowering drugs reduced heart attacks, but increased deaths. That is not a success story. One of my mentors often invoked the old saw about a surgeon who informs a horrified wife that the operation was a success, but the patient died. Medical reports can be similar, touting benchmarks like heart attacks or cholesterol levels while ignoring what matters—living longer and better.
Therefore, first, when reading studies it is crucial to recognize surrogates like blood pressure and cholesterol. People want to avoid high blood pressure and high cholesterol because they want to live longer and better. Which is why studies had to show blood pressure drugs could help them achieve those aims. And they did.
People taking the drugs in trials had fewer strokes (a major source of disability and suffering) and died less. Dying less and better quality of life—not lower blood pressure—is why antihypertensive drugs are considered effective.
Second, statins probably do help people after a heart attack or stroke. People who have had heart attacks or strokes have cardiovascular disease, and are therefore in the highest risk category for future strokes or early death. The best treatment for people with heart disease is to quit smoking, improve diet and exercise, tame blood pressure, and even lower cholesterol. In that order. To be sure, even for this group studies show the impact of lowering cholesterol is frustratingly small (96% reaped no reward in statin studies). Still, the benefits can outweigh the harms, making cholesterol-lowering a reasonable addition to other treatments.
But a defining claim of the Lipid Hypothesis is that cholesterol causes heart disease—not that it’s a small-time contributor in people who already have it. For the Lipid Hypothesis to be right, as cardiologists and the NIH insisted, lowering cholesterol should give healthy people, not just heart patients, demonstrably longer and better lives.
This pivotal distinction, however, led to a prickly dilemma for drug companies. Because they didn’t care whether the AHA was presumptuous, or jumped ahead of the evidence. They needed the Lipid Hypothesis to be right for a different reason: If it was, their target could be everyone—not just heart patients. If even healthy people should be on statins (every day for the rest of their lives) the pills could be endless profit machines.
So they did a switcheroo.
The Data: WOSCOPS
The West of Scotland Coronary Prevention Study (WOSCOPS) is widely known as the first mega-trial to show statins work for ‘primary prevention’ patients, i.e. people who do not already have heart disease.
But why did the drug companies travel to the west of Scotland for this? Because the region was known to have among the world’s highest burdens of undiagnosed heart disease. And genetically high risk. And obesity. And smoking. And sedentary lifestyle. Especially in the west. Particularly among men.
The average participant in WOSCOPS was an obese, sedentary, smoking Scotsman (no women allowed) with a cholesterol level of 272. Participants were, in other words, diligently screened to create a group that was not even remotely similar to what most physicians and public health researchers call ‘primary prevention’.
The researchers acknowledged this in a 1992 methodology paper. “The term ‘primary prevention’ is a misnomer in this type of study since all subjects will have coronary artery disease to a greater or lesser degree,” they admitted. Then, three years later, when reporting their results in the prestigious New England Journal of Medicine, the authors described their study as falling “strictly into the primary-prevention category.”
This brazen bait-and-switch was only seen by the few who read the technical background papers. But it is also what makes the findings from WOSCOPS so jarring—because the drugs still failed. Despite lowering LDL cholesterol by 26%, and despite five years of statins for sedentary smoking men with astronomical cholesterol, immutable genetic risk, and underlying heart disease, neither deaths nor strokes were less common in the men who took statins.
The one statistical difference favoring statins was in nonfatal heart attacks, at 1.6%.[2] This meager difference is what led companies and cardiologists everywhere to declare victory. Coming in the shadow of the fibrate debacle this was an audacious bit of spin. After all, the fibrates had proven that a drop in nonfatal heart attacks did not reliably signal better health, and could even be accompanied by increasing deaths.
But statins, it seemed, had not increased deaths. Which raised a new question.
What is the trade-off? All drugs have serious harms (there’s no free lunch in pharmaceuticals). The question, then, is how many people taking a drug can be expected to experience harms that worsen their life. Statins, it turns out, cause diabetes in about 0.5-2% of people taking them, and chronic muscle damage and pains in at least 5%.[3]
When comparing harms and benefits, it is also worth noting that, despite their frightening name nonfatal heart attacks in trials may be more important on paper than in patients’ lives. Extensive research has shown that heart attacks recorded in treatment trials tend to be minor, do not shorten life, and have no association with serious disability or death. In fact they often trigger healthy habits like exercise and eating right, leading to potentially longer and better lives.
And while heart attacks are, at least in theory, something to avoid, what if the alternative is diabetes and muscle damage?
Described mathematically, statins help about 1 in 60 people avoid a nonfatal heart attack, but cause diabetes for up to 1 in 50 and muscle problems for 1 in 20. These harms, occurring in roughly 7% or more of people who take statins, outpace the benefit more than four times over. But it’s worse: The 1.6% benefit is a best-case scenario derived from genetically star-crossed men with heart disease. Everyone else can expect an even lower rate of return.
So what does it all mean? First and foremost, it means we’re fighting over scraps. WOSCOPS, and all of the data since, showed statins did not help with the real prize, living longer and better. They neither lengthened life nor prevented strokes in true primary prevention. Then, for the rare person who avoided a nonfatal heart attack, more than one person also contracted diabetes, a chronic and potentially devastating condition. Add to that another three or more people with muscle damage, and the scales seem hopelessly tipped.
Shown these benefits and harms, how many would take a drug every day for the rest of their lives?
Perhaps most importantly, WOSCOPS answered the biggest question about the Lipid Theory: Either the theory is wrong, or the impact of lowering cholesterol was so small that 5,000 men with heart disease wasn’t enough to find it.
The Data: Statin Studies After WOSCOPS
As of this writing WOSCOPS has been cited more than 7,000 times in scientific journals, paraded as proof of a life-saving effect the study never found. The AHA and other guidelines continue to routinely cite WOSCOPS when recommending statins for primary prevention. But WOSCOPS is not alone. Dozens of company-run statin studies have been conducted and almost all, like WOSCOPS, used cutesy design tricks like ‘run-out’ phases (removing people who experience adverse effects), while ignoring or failing to report diabetes and muscle problems. And like WOSCOPS, all of the company trials enrolled ultra-high-risk people.
One landmark review of studies, written by company-funded researchers and covering 170,000 study participants and 27 trials, is routinely cited by guidelines. The authors conclude the benefit of statins, at 1.1%, “greatly exceeds any known hazards” for primary prevention. But even this paltry 1.1% combined lots of endpoints together, more than half of which were procedures like stents, a notoriously biased outcome.[4]
Focusing on what matters, the statins did not reduce deaths in people who live at typical primary prevention risk levels.[5] [6] As for strokes, the paper doesn’t report total numbers.[7] But a review by the United States Preventive Services Task Force estimates (optimistically) a 0.32% decrease in strokes with statins. Unfortunately this includes participants with heart disease, contaminating the math for primary prevention. Even accepted at face value, however, it means fewer than 1 in 300 people who took a statin for 5 years avoided a stroke.[8]
These numbers tell an astounding story: Even data curated and laundered by drug companies show a) the drugs neither improved nor extended lives, and b) they harmed more people than they helped. But sponsored researchers, talking heads, and doctors everywhere have for years painted a different picture. Confirmation bias is powerful, and statin reports were spun to confirm a manufactured consensus. And yet the irony is that statin trials weren’t eligible to confirm anything.
They were the second test of the Lipid Hypothesis after the fibrates. And the theory failed. Again.
It’s Not Just Statins
Fibrates and statins are among the best-known cholesterol-lowering drugs, but the PCSK9 inhibitors are even more jaw-dropping. A lab creation crafted to collect and clear cholesterol, these drugs do something scientists did not think possible. They nearly eradicate cholesterol from the bloodstream.
The statins block the enzyme HMG-CoA reductase, lowering cholesterol by about 20-30%. This was revolutionary. But the PCSK9 drugs drop levels by up to 80%. For people who start with a cholesterol of 200 the drugs routinely drop it to 50 or lower.
If the Lipid Hypothesis is true, these new-fangled techno-gems should be saving millions of lives. But they’re not. Because they also failed. Despite endless fanfare, a furious advertising blitz, and a Cadillac price tag, comprehensive reviews show that even among ultra-high risk secondary prevention patients, the drugs have no impact on mortality and at best a less than 1% effect on strokes. In other words the PCSK9 drugs represent a third, even more convincing failure of the Lipid Hypothesis.
But that’s not all.
The same is true for CETP inhibitors, also known as the trapibs, which have the kind of dramatic cholesterol effects that make a lipidologist jump for joy. The drugs slash LDL, the ‘bad’ cholesterol, while boosting HDL, the ‘good’ stuff. In trials this translated into exactly zero reduction in heart problems, but a single year of treatment did inexplicably increase deaths by 60% relative.
On an absolute scale, this meant for every year of treatment 1 in 250 people taking the drug died because of it, while no one saw a single benefit of any kind. Thus despite having theoretically ideal effects on cholesterol—even better than statins—the trapib drugs turned out to be quiet killers.
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Why Doesn’t Lowering Cholesterol Work?
Framingham’s final report on cholesterol was a clear flag. But many papers have since confirmed and helped elucidate the failure of the Lipid Hypothesis. In 2015 the Journal of the American Medical Association published a paper studying people with a first-time heart attack. While Framingham and other studies studied healthy people, the JAMA paper examined people with a new diagnosis of heart disease.
As expected, the study showed nearly a third of first-time heart attack victims were smokers, a rate about twice that among the US general population. Also expected, more than half had high blood pressure, compared to just 29% in the general population. And almost two thirds were overweight or obese, nearly double the US population rate.
But another finding stood out: just 28% of people having their first heart attack had high cholesterol—and that was less than the prevalence in the general population, at about 34%. High cholesterol therefore stood alone among ‘risk factors’ as more common in the general population than in people who just had their first heart attack.
When people with a first heart attack are less likely to have high cholesterol than everyone else, is it a ‘risk factor’? And if 28% had high cholesterol, then 72%, nearly three quarters of people having their first heart attack, had normal cholesterol.
Finally, in 2025 history’s largest and most important study of cardiac risk factors was published in the vaunted New England Journal of Medicine, and it closed the door on cholesterol for good. With 2 million participants from 33 countries and up to nearly 50 years of follow-up, the report confirmed the Framingham finding that cholesterol is not associated with early death—then it went a step further.
Of the five classic risk factors proposed by Framingham, hypertension, smoking, diabetes, obesity, and high cholesterol, the data found that only elevated cholesterol (as defined by the AHA, an LDL of greater than 130) was a negative risk factor. In other words, it was protective against both heart problems and death. In this largest, most rigorous study ever done, having an elevated LDL cholesterol was associated with living longer, and fewer heart problems.
From the 2025 NEJM study, the figure above shows associations with heart disease (top box), and mortality (bottom box) for the five classic risk factors. I have placed red circles to highlight the places in the data where the bars go to the left of the line representing zero, suggesting protection rather than risk.[9]
Much like in the Framingham’s data, the other four classic risk factors were confirmed. Smoking and diabetes were the most powerful (by far), taking 5-6 years of life each, while high blood pressure and obesity were less powerful, but still on the ‘danger’ side of the ledger.
In the study’s primary figure, however, it is plain to see that elevated cholesterol stood alone—not just debunked as a risk factor, but in fact protective against both death and heart disease.
These findings, combined with statin trial data, mean lowering cholesterol for primary prevention isn’t just a waste of money (though the numbers are staggering—2002-2018 Americans spent almost half a trillion on statins, then $500m/year more on PCSK9s). It is also dangerously misleading. Smoking, diabetes, diet, physical activity, and high blood pressure are powerful, proven risk factors that can be modified, making them worthy targets. Yet cholesterol has been a scapegoat for so long it is routinely the first thing people defer to. “Heart attack? Nah, my cholesterol is fine.” But 72% could have said the same thing minutes before their first heart attack.
They also might have used this misplaced confidence to justify complacency. And there’s evidence to suggest they do. People who take a statin become more sedentary and eat more. The former may be related to muscle pains and damage, and both are frightening.
So why did so many people with a first heart attack have normal cholesterol? Why isn’t cholesterol the risk factor we thought it was?
There’s lots of biochemistry and physiology, most of it not clarifying enough to dive into, but a few obvious points deserve attention. First, in 2014 an advisory group reversed the U.S. government’s long-held position on dietary cholesterol. After an extensive review of data they concluded “cholesterol is not considered a nutrient of concern.” Alas, it seems, humans are not rabbits, and atherosclerosis, a sign of ageing across the animal kingdom, is not synonymous with heart disease.
For starters, cholesterol molecules in food are not the same as those in blood. Each ingested cholesterol molecule is broken down and most are reconstituted, after which the body chooses their destination. Only a fraction goes to the bloodstream, and only a fraction of those is destined for artery walls. And when they arrive in the artery wall they constitute just a fraction of the plaque in which they reside, alongside collagen, overgrown smooth muscle cells, cell debris, fibrin, and other proteins.
The small fraction of a fraction represented by cholesterol probably explains why statins may help a small percentage of people at highest risk, those with heart disease. But it is conspicuously inconsistent with the Lipid Hypothesis, which suggests cholesterol is the predominant cause. And it cannot begin to overcome the dangers and downsides of taking statins for everyone else.
What, Then, Does Matter?
Exercise.
Unfortunately, lifestyle interventions like diet and exercise are impossible to study as rigorously as pills. For starters there is no placebo version, making comparisons messy and conclusions hard to prove. But data strongly suggest exercise adds years, perhaps a decade or more. Better yet, those tend to be high quality years. Compare that to a report of statin studies which found the drugs added an average of roughly four days of life (at best, i.e. in secondary prevention).
Diet may be crucial too. As with exercise, the data are often shaky since studies randomizing people to eat only broccoli vs only steak for decades won’t happen. Which is why food headlines flip-flop constantly. But in a few good trials there have been victories. Chief among them is the Lyon, or Mediterranean, Diet. And the name is misleading because it’s not a ‘diet’, it’s more like a vacation on the French Riviera. There is little about the Mediterranean Diet that includes sacrifice or suffering. And yet it’s many times more powerful than any drug to prevent heart attacks, strokes, and deaths. As Rita Redberg, a brilliant researcher and cardiologist has said, “If the Mediterranean Diet were a pill, it would be a blockbuster.”
Even better, Mediterranean Diet wasn’t compared to a typical Western diet of highly processed foods. In its first major trial, it was compared to the American Heart Association diet which has, for decades, been aimed at (you guessed it) lowering cholesterol. And while this is now a debunked approach it is probably still healthier than what many Westerners eat. If the Mediterranean Diet prevents heart attacks, strokes, and deaths compared to the AHA diet, imagine how powerful it can be for everyone else.
The cholesterol obsession has also had tragic consequences. In the 1980’s the American diet began transitioning away from cholesterol and toward sugar and carbohydrates. The American body transitioned in parallel. The US is now mired in an epidemic of overweight and obesity. Revelations from 2016 show the sugar industry quietly paid for this transition, and the AHA played ball. In 2015 cardiologist Dr. Barbara Roberts explained the AHA’s racket of charging millions to manufacturers for certifying their sugar-packed foods with a ‘heart healthy’ stamp of approval, based on cholesterol content.
Why Did Doctors Fall For It?
A number of researchers, scientific authors, cardiology experts, and others, have written about and explored the factors that drove the statin deception. For those interested in a more technical view, what follows is an explanation of the most common sleights of hand in the statin trials.
In trials only about 1%, or 1 in 100 who took a statin, lived longer and that occurred only among people with known heart disease. The companies often reported these benefits, however, as a “10% proportional reduction.” If 10% of participants who took a placebo died compared to 9% of those taking a statin, this is a 10% proportional reduction. If you start at 10 and drop to 9, you’ve cut 10% off.
The drug makers therefore buried their claims in massive pools of data and presented them in relative, rather than absolute terms. Doctors bought in, partly because of the imprimatur of media like the New England Journal of Medicine (where the editors were often among the ‘experts’).
Another clever trick remains hidden in plain sight. The largest and most cited statin reviews were written by the Oxford University-based ‘Cholesterol Treatment Trialists’ group. Recall this group will not, because of their agreements with industry, show anyone else the original data. But their reviews share a peculiar characteristic: they show results per-cholesterol reduction.
Instead of reporting deaths on statins vs deaths on placebos, they show results based on cholesterol level. Differences in the number of heart attacks, for instance, are presented as ‘number of heart attacks avoided per 1 mmol/L reduction in LDL’. They do the same for every other endpoint including stents, strokes, and more. Results are never shown by comparing the actual numbers from each group.
The authors claim this allows for equal comparisons across trials of different doses and different effects. But this is unique. Landmark trials proving blood pressure medicines work did not show their effects per-blood pressure reduction. This type of result, sometimes of academic interest, can help tailor treatment or tweak dosing decisions. But it is simply never the determinant of whether a drug works.
That’s because different people have different responses to antihypertensive drugs. The same is true for cholesterol, and anything else. Which is why these outcomes are called ‘surrogates’. A drug’s important effects—living longer and better—are often untethered to the surrogate they target. For some people even a small drop in blood pressure may be life-saving. Others can have a disabling stroke despite perfect blood pressure control. And during the fibrate trials cholesterol dropped while deaths rose. Had results in the fibrate trials been reported based on per-cholesterol-reduction, the increase in deaths may have been missed.
Moreover, recent research shows in the case of statins, the LDL cholesterol reductions the drug induces may have little or no relationship to the clinical effects that matter. Which means it is deeply misguided, and potentially very misleading, to present statin data based on per-cholesterol reductions.
The crucial question when reading a trial report is therefore whether a drug, and especially a statin, prevents important events, and how many. No fancy dancing, no statistical converting, no per-this or per-that. Did it work and how much?
The incredible, singular pass given the statin drugs is baffling. It may be part of a broad and unthinking acceptance of cholesterol theory. After all, if cholesterol is what matters why not report deaths and strokes not as an end in themselves, but according to the real prize, cholesterol reduction?
Of course, the drug makers did more than just play with statistics and flood the literature with disinformation. Company reps still buy meals for doctors’ offices and staff every day. They continue to ply physicians with trips, ‘conferences’, lectures, gifts, and shiny quid pro quos. They also make FDA-approved commercials that lead patients to beg doctors for $6,000-a-year cholesterol drugs that are proven not to work. All of which, combined with the trickery above, has been more than enough to penetrate the minds of the best and brightest providers in the world.
Conclusion
Statins are a reasonable drug for Familial Hypercholesterolemia, a genetic mutation in which levels are often 350 and above. And, arguably, for people with established heart disease, though there are more powerful and important steps to consider first (exercise, diet, BP control, quitting smoking, etc.).
And statins are, hopefully, not killers. I’m treading carefully here, since there are people still working to make the statin data available and I do not yet know what an honest reading of the numbers will show. History suggests companies that hide data do so for a reason. There are certainly important side effects with statins, including muscle problems and diabetes, but so far the data haven’t looked like they did with fibrates, where heart attacks dropped and deaths rose. So that’s nice.
The tragedy of FDR’s untreated hypertension spawned the Framingham project, which confirmed that early death and hypertension are associated. This, in turn, led to rigorous trials testing medicines. The approach was methodical, careful, and scientifically sound. Studies at each stage yielded consistent, unassailable findings confirming high blood pressure causes heart disease, and lowering it saves lives.
But the final Framingham findings for cholesterol were not like hypertension, and they came just as the cardiology community was declaring cholesterol its next moonshot. But the Framingham results were a red light that dieters, doctors, and drug makers blew right through. Some were filled with the hubris of prior success, others thirsty to monetize a cultural myth, but most were just credulous and complicit.
And all they had to do was read the studies. By distracting from the forest while parading the trees, statin makers pulled off an uncanny deception. But with an eye to what truly matters, there’s just no way around it: The cholesterol theory failed.
FOOTNOTES:
[1] It’s worse. 50K is the estimate from one study attempting to gauge the damage done just by misrepresenting one drug, Merck’s Vioxx. The opiate crisis is obviously associated with dizzying numbers (hundreds of thousands) of deaths, and it’s nearly impossible to precisely attribute which of these are a direct result of oxycontin misrepresentations. With Pfizer’s Neurontin the subterfuge has mostly led to a different crisis: more than a decade of irrational prescribing and misleading publications about a drug that simply doesn’t work any better than placebo for the overwhelming majority of those prescribed it. See John Abramson’s second book ‘Sickened’ for more. Abramson, an expert witness in numerous legal cases, is one of a small handful of people in the world who has seen the original trial data behind many drugs.
[2] In the original paper the numbers are 6.5% vs 4.6%, for a 1.9% difference. But this included ‘silent MIs’, i.e. heart attacks that are never felt or experienced by patients and instead are diagnosed retrospectively by cardiologists interpreting EKGs performed at routine visits. This method of diagnosing heart attacks has now been largely debunked, since EKGs often change for reasons other than ‘silent’ heart attacks. I therefore use a back-calculation from data in WOSCOPS Table 2, subtracting the silent MIs, to find 5.0% vs 3.4%.
[3] In a carefully designed randomized trial statins caused muscle damage and pains in 5% taking the drugs. However the duration of therapy in the trial was 6 months. Compare this to the benefits of statins, measured over 5-7 years in most studies like WOSCOPS. Therefore 5% is a very conservative estimate, since it is highly likely that as statin therapy continues the proportion of people experiencing these muscle effects will rise. If the effect was linear over time the equivalent percentage who get muscle damage and pain due to statins would be 50% (though it may well not be linear). Compared to the 1.6% who avoid a nonfatal heart attack after 5 years of statins, this would be a 17 times greater chance of experiencing a harm. As it stands, even using the most conservative under-estimate, the harm would be more than three times as frequent as the benefit.
[4] A seminar in research deception could be given on how stents create and falsely inflate ‘benefits’ when used as an endpoint in most cardiac studies. For starters, cardiologists who place stents are strong believers in the cholesterol theory. So when cholesterol levels are higher, those cardiologists are both more likely to believe patients ‘require’ stents, and more likely to place them. Statins lower cholesterol. Therefore stent procedures become less likely on this basis alone. Thus unless a statin failed to lower cholesterol levels there will always be more stents in the group taking statins. Second, and most importantly, unless one is in the midst of a (big) heart attack stents are proven not to extend life or prevent future heart attacks. This means that placing stents didn’t stave off an impending heart attack or death, as was first assumed when this metric was used as an endpoint in trials during the 1980s and 1990s. They don’t do that, and therefore adding them in to the composite endpoint improperly implies that they are some sort of surrogate for a prevented death or heart problem. They’re not. This second point alone (in addition to the cholesterol-dependent caprice with which they are placed) makes them a totally inappropriate and deeply misleading metric in trials of preventive therapies.
[5] Page 14 of the online supplement accompanying the report shows for those at <10% risk over 5 years (already higher than most primary prevention groups) there was no difference in mortality between taking a placebo and a statin.
[6]Also worth noting is most people taking statins in the community, as opposed to in studies, are healthy. One pair of UK researchers studied statin trials to determine the drugs’ effect on healthy people. Their conclusion: “No such studies have been conducted.” Other researchers have also documented the gaps between published studies and how the drugs are used in practice.
[7] In the data supplement accompanying the review, on p9 strokes are listed by subtype (ischemic and hemorrhagic), but not combined together. In the lowest risk group (primary prevention) there is no statistical reduction in ischemic strokes, and for the next higher risk group the results are borderline. This suggests no benefit, but no calculation combining the two groups is shown. Moreover, when combined with hemorrhagic strokes, which tend to be far more disabling and were consistently higher in the statin groups, it is likely there is no benefit and there may even be harm. Only about half of ischemic strokes are disabling, while most hemorrhagic strokes are.
[8] This too is inflated, since a) it’s a good bet the one person who avoided a stroke was in the high-risk category, i.e. not a primary prevention patient, and b) half of nonfatal strokes leave no residue or disability.
[9] First, the source for this is a March, 2025 NEJM publication. For the nitpickers (I love you so!) who are wondering about what the ‘regional SD’ numbers represent, this is the study authors’ attempt to find a way of making cholesterol look like a risk factor. I would imagine they were flabbergasted to find that it was the opposite, and went searching for a mathematical tweak to address such heresy. The way they did it was to move the goalposts. Instead of using LDL >130 mg/dL as their cutoff for cholesterol (the AHA’s cutoff), they switched it two standard deviations above the regional average. In other words, people whose cholesterol is in the top 2% of all cholesterol values in the region. In the U.S., for instance, this would start at an LDL of roughly 190, and would include all of the people with Familial Hypercholesterolemia, whose LDL’s can be as high as 500 or more. Basically, rare and egregiously elevated levels that are, IMHO, very reasonable to consider treating—which is why no one debates about it. But it does point out, I think, a pretty interesting fact: the top 2% of outliers with exceptionally elevated LDL levels are being thrown in with the larger population of people who are ‘above the AHA cutoff of 130’. Which means that rare outlier cholesterol levels are contaminating the pool of people with much more normal LDL levels like 130-170, and making their risk look much higher than it is. Which, of course, probably means that if we were able to remove them from the calculations in the 2025 paper, an ‘elevated LDL’ would be even more protective, adding more years of life and reducing cardiac problems even more.
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